1. Field of the Invention
This invention is directed to novel substituted aminobenzamidinosuccinyl lactone derivatives which inhibit aggregation of platelets. This invention is also directed to a pharmaceutical composition comprising these compounds. This invention is further directed to a method for inhibiting platelet aggregation.
2. Related Background Art
Platelets are cellular components of the blood responsible for coagulation and clot formation. Fibrinogen is a glycoprotein which binds to platelets in the coagulation mechanism. When a blood vessel receives an injury, platelets initially form a monolayer adhering to collagen in the underlying subendothelial matrix. The adherence of the platelets leads to their activation according to a process in which GP IIb-IIa receptors (a membrane glycoprotein) undergo a conformational change to allow for fibrinogen binding. The platelets then bind fibrinogen, which fibrinogen then adheres to additional platelets, forming a thrombus. At the same time, factor Xa mediates the cleavage of prothrombin to thrombin. Thrombin cleaves fibrinogen to fibrin, which forms a stable clot. Naturally occurring plasmin eventually cleaves fibrin and dissolves the clot. Inhibitors of different steps in this pathway are effective in modulating or preventing thrombus formation and/or clotting.
It is also known that fibronectin, a large glycoprotein and a major extracellular matrix protein, also interacts with fibrinogen and fibrin, as well as with other structural molecules such as actin, collagen, and proteoglycans. It has been found that relatively large peptide fragments found in fibronectin's cell-binding domain have cell-binding activity. See U.S. Pat. Nos. 4,517,686; 4,589,881; and 4,661,111. Additionally, short peptide fragments of the same molecule have been found to have cell-binding activity, or activity inhibiting cell-binding when placed in solution or suspension, presumably because they bind to the cell and prevent its binding to the substrate. See U.S. Pat. Nos. 4,578,079 and 4,614,517. Other synthetic peptides have also been used to inhibit binding of fibrinogen to platelets. See, e.g., Koczewiak et al., Biochem. 23:1767-1774 (1984); Plow et al., Proc. Nat'l Acad. Sci. 82:8057-8061 (1985); Ruggeri et al., Proc. Nat'l Acad. Sci. 83:5708-5712 (1986); Ginsberg et al., J. Biol. Chem. 260:3931-3936 35 (1985); Haverstick et al., Blood 66:946-952 (1985); Ruoslahti and Pierschbacher, Science 238:491-497 (1987); U.S. Pat. No. 5,344,957; European Patent Application 275,748; and European Patent Application 298,820.
Compounds containing an amidino group attached to an aromatic ring are also known to have cell-binding activity.
European Patent Application 496,378 discloses amidinobiphenyl compounds which inhibit cell-cell and cell-matrix interaction and are thus useful for treating thrombosis, cerebrovascular diseases, pulmonary embolisms, myocardial infarction, arteriosclerosis, osteoporosis, and tumor metastases.
European Patent Application 445,796 discloses amidino-substituted acetic acid derivatives which have inhibitory action on the bonding of adhesive proteins to platelets as well as on platelet aggregation and cell-cell adhesion.
European Patent Application 372,486 discloses N-acyl .beta.-amino acid derivatives and their salts. These compounds are said to be useful for inhibiting platelet aggregation in the treatment of thrombosis, stroke, myocardial infarction, inflammation, arteriosclerosis, and metastasis.
European Patent Application 381,033 discloses amidinoaryl or guanidinoaryl substituted alkanoic acid derivatives useful for the treatment of thrombosis, apoplexy, cardiac infarction, inflammation, arteriosclerosis, and tumors.
PCT Application WO 95/06038 discloses cyclic ureas substituted by an amidinophenyl group and a .beta.-amino acid. These compounds are useful as platelet aggregation inhibitors.
PCT Applications WO 93/18058 and WO 95/06038, and European Patent Applications EP 542,708 and EP 539,343 disclose amidinobenzenaminosuccinyl acid derivatives useful as platelet aggregation inhibitors.
PCT Applications WO 94/00424, WO 93/12074 and WO 93/12103 disclose phenylamidine alkanoic acids and lactones useful as platelet aggregation inhibitors.
PCT Application WO 94/22820 discloses amidinophenyl pyrrolidinones, piperidinones, and azetidinones useful as platelet aggregation inhibitors.
U.S. Pat. Nos. 5,220,050 and 5,344,957 disclose amidinophenyl-substituted .beta.-amino acid derivatives which are useful as platelet aggregation inhibitors.
J.A. Zablocki et al., J. Med. Chem., 38, 2378-2394 (1995) and European Patent Application No. 502,536, disclose aminobenzamidino succinyl compounds which are useful as platelet aggregation inhibitors.
The present invention is directed to novel aminobenzamidinosuccinyl lactones which inhibit platelet aggregation.